Temozolomide analog PMX 465 downregulates MGMT expression in HCT116 colorectal carcinoma cells

Yang, Zhikuan; Wei, Danping; Liu, Feifei; Liu, Jing; Wu, Xiaoming; Stevens, Malcolm F. G.; Bradshaw, Tracey D.; Luo, Ying; Zhang, Jihong

Abstract

The efficacy of temozolomide (TMZ) treatment for cancers is currently limited by inherent or the development of resistance, particularly, but not exclusively, due to the expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) in a significant proportion of tumours. We have found that TMZ analogue C8-methyl imidazole tetrazine (PMX 465) displayed good anticancer activity against the colorectal carcinoma HCT116 cells which are MGMT-overexpressing and mismatch repair (MMR)-deficient. In this study, we found that PMX 465 could downregulate the expression of MGMT in HCT116 cells at the protein and mRNA levels. We found that PMX 465 could reduce MGMT expression by increasing the binding of wild-type p53 to the MGMT promoter and reducing the binding of Sp1 to the MGMT promoter.

Citation

Yang, Z., Wei, D., Liu, F., Liu, J., Wu, X., Stevens, M. F. G., Bradshaw, T. D., Luo, Y., & Zhang, J. (in press). Temozolomide analog PMX 465 downregulates MGMT expression in HCT116 colorectal carcinoma cells. Journal of Cellular Biochemistry, https://doi.org/10.1002/jcb.26674

• Journal Article Type: Article
• Acceptance Date: Jan 11, 2018
• Online Publication Date: Jan 13, 2018
• Deposit Date: Jan 22, 2018
• Publicly Available Date: Jan 14, 2019
• Journal: Journal of Cellular Biochemistry
• Print ISSN: 0730-2312
• Electronic ISSN: 1097-4644
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1002/jcb.26674
• Keywords: PMX 465 ; O6-methylguanine-DNA methyltransferase ; p53 ; Sp1 ; Colorectal carcinoma
• Public URL: https://nottingham-repository.worktribe.com/output/904361
• Publisher URL: http://onlinelibrary.wiley.com/doi/10.1002/jcb.26674/pdf
• Additional Information: This is the peer reviewed version of the following article: Yang, Zhikuan and Wei, Danping and Liu, Feifei and Liu, Jing and Wu, Xiaoming and Stevens, Malcolm F. G. and Bradshaw, Tracey D. and Luo, Ying and Zhang, Jihong (2018) Temozolomide analog PMX 465 downregulates MGMT expression in HCT116 colorectal carcinoma cells. Journal of Cellular Biochemistry . ISSN 0730-2312 , which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/jcb.26674/pdf. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving
• Contract Date: Jan 22, 2018